Steroids may do more harm than good in some cases of severe asthma
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The research was published in the journal JCI Insight.
Asthma is a lifelong disorder characterized by airway inflammation that leads to wheezing, breathlessness and coughing. Inhaled corticosteroids can reduce airway inflammation, but these drugs are ineffective in 5 to 10 percent of patients with severe asthma.
"The current therapies are inadequate for a subset of patients with a severe form of asthma," said the study's co-senior author Anuradha Ray, Ph.D., professor of immunology and medicine and Endowed Chair in Lung Immunology at Pitt's School of Medicine. "We need to better understand their underlying disease and why they are poorly responsive to corticosteroids in order to identify novel targets for future therapies."
The researchers had previously shown that increased levels of the inflammatory protein interferon-gamma are produced in the airways of about half of severe asthma patients. Using a mouse model of severe asthma, the researchers also showed that interferon-gamma was responsible for poor lung function.
In the new study, they investigated whether interferon-gamma signaling is responsible for the poor response to corticosteroid therapy of some severe asthmatics. The work focused on CXCL10, an inflammatory protein that is induced by interferon-gamma and recruits the immune cells that produce it, perpetuating the cycle of inflammation.
CXCL10 was elevated in the lung cells of about half of severe asthma patients treated with a high dose of corticosteroids. In addition, CXCL10 levels were higher in severe asthmatics than in patients with milder asthma whose symptoms were managed well by corticosteroids or other treatment modalities.
When the researchers broke all asthma patients down into two groups - high and low CXCL10 - they found that the high CXCL10 group had worse asthma control, as evidenced by more emergency department visits and asthma flares in the past year.
Next, the team used cultured immune cells to show that corticosteroids, which have broad anti-inflammatory and immunosuppressive functions, fail to suppress CXCL10 gene expression in immune cells. They found that this occurs because of a surprising mechanism - corticosteroids actually stabilize the signal from interferon-gamma that stimulates CXCL10 production.
"Our findings show that CXCL10 is elevated in some patients with severe asthma and that corticosteroids have little impact on its production," said co-senior author Sally Wenzel, M.D., professor of medicine in Pitt's School of Medicine and director of the University of Pittsburgh Asthma Institute at UPMC. "While corticosteroids are the mainstay asthma treatment, our findings suggest that these medications are of limited help to patients with high levels of interferon-gamma and CXCL10, and may even be harmful over time."
The team plans to further investigate this pathway in search of ways to block the inflammatory loop perpetuated by CXCL10 and interferon-gamma.
"Over the next few years, we also hope to show that CXCL10 can be used as a biomarker in the clinic to help identify patients who will not respond to corticosteroids, sparing them from the significant side effects of these medications," Ray said.
This is very interesting even if a bit technical . I can only talk from experience but if I had known how having a maintenance dose of steroids would effect me 15 years on I would never have agreed .My weight has gone from 8 stone to 13 plus stone despite watching my diet better .As a result I am now type 2 diabetic with complications,have onset oesteoporios and my digestive system is shot .The problem is that basically my body is addicted to them so that when the doctors tried to take me off them it went into shock and I collapsed . I have just started a new treatment which involves traveling a 100 mile round trip to have injections once a month with the view to reducing my steroids right down and hopefully eventually off them altogether .Touch wood it seems to be helping as I find that I can do a bit more without an asthma reaction on a weekly basis .The test will come in a couple of months when they reducey steroids for the first time in about 5 years
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Well they started to reduce my steroids and I am down to nearly half what it was. Touch wood I am doing alright, bit breathless in the evenings but I can cope with it. Also changed hospital going to for monthly injections to one half the distance away which makes it better
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Good news I hope it continues
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Update, I am down to a third of the dosage of steroids I was on before. I can walk the dog twice as far as before have largely done away with my reliance on my rollater, making plans to go away solo (starting with a weekend at Weymouth our nearest seaside resort). My husband left last November and at the time it knocked me for 6 but now I can say it was a blessing in disguise. I have lost about a stone in weight and having my hair cut short for the first time in probably 40 years tomorrow I am enjoying life and making plans for the future which I could never have done a year ago
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